Behavioural and biochemical consequences of persistent overstimulation of mesolimbic dopamine systems in the rat

Abstract

Rats, separated into high and low activity responders on the basis of their response, in terms of hyperactivity, to peripherally administered (−) N- n-propylnorapomorphine [(−)NPA] were subject to chronic infusion of dopamine or its solvent bilaterally into the mesolimbic system (nucleus accumbens) for 13 days via Alzet osmotic minipumps. Both high and low activity responders exhibited enhanced spontaneous locomotor activity during the infusion of dopamine (but not solvent) whether measurements were made over a 180-min period in individual photocell cages or over 24 hr via Automex activity meters in a grouped situation. The ability of (−)NPA to stimulate locomotor activity was virtually abolished in both high and low activity responders from the second day of the infusion of dopamine to its termination. This reduction continued for up to 42 days following withdrawal of dopamine from the high activity animals. In contrast, the animals initially classified as low activity responders gave markedly enhanced activity when challenged with (−)NPA 2–3 weeks after withdrawal from dopamine. Hyperactivity, caused both by infused dopamine and by peripherally administered (−)NPA, was shown to be selectively antagonized by neuroleptic agents. Solvent infusion did not alter behavioural responding from control either during or after infusion. Radioligand binding assays using[ 3H]NPA showed three clear differences between the two selected groups of rats. First, there were significantly more [ 3H]NPA binding sites in the mesolimbic tissue of normal high activity responders than normal low activity animals; secondly, chronic dopamine infusion increased [ 3H]NPA binding sites for low activity animals at a time when their responses to (−)NPA were markedly enhanced; thirdly, chronic infusion of dopamine decreased the numbers of [ 3H]NPA binding sites in high activity responders at a time when their responses to (−)NPA were markedly reduced.